1. Field of the Invention
The present invention is in the field of medicinal chemistry. In particular, the present invention is related to a sunrising new method to treat or prevent Alzheimer's disease by dietary restriction of carbohydrates and/or administration of an agent which causes reduction in serum insulin levels.
2. Related Art
According to a recent review by Mairin B. Brennan published in Chemical and Engineering News 75(3):29-35 (1997), roughly 4 million people in the United States have Alzheimer's disease. Inherited or not, the disease manifests itself with progressively impaired memory leading to mental confusion as the disease systematically kills off nerve cells in the brain. (Brennan.)
The devastating consequences of Alzheimer's disease has led to a prodigious effort to identify drugs that might be useful for treating the condition. Two drugs are currently available for treating Alzheimer's symptoms. Cognex (tarcine), sold by Parke-Davis and CoCensys Inc. was approved by the FDA in 1993. Aricept, sold by Eisai of Japan, was approved late in 1996. Both drugs are designed to improve memory and cognition in the earlier stages of the disease. (Brennan.)
Alzheimer's disease is characterized by amyloid plaque that deposits around and between nerve cells in the brains. The plaques contain fibrillar aggregates of a small peptide called amyloid β-peptide. These plaques are centers for the degeneration of nerve endings. Whether the fibers themselves are themselves toxic is somewhat controversial, in view of transgenic animals which have been engineered to express amyloid β-peptide. These mice make amyloid deposits, and there is damage to nerve cells around the plaque, however, no further neuronal loss is seen in these mice. Thus, there appear to be other mechanisms involved. (Brennan.)
Whether the amyloid plaques are the cause or the consequence of the disease is a perplexing question according to Brennan. However, “all genetic routes to Alzheimer's known today, ‘act by increasing production or deposition of amyloid—or both,’” quoting Dennis J. Selkoe, professor of neurology and neuroscience at Harvard Medical School. Laedtke, et al., Clinical Research 42(1):65A (1994), have also noted an epidemiological correlation between the deposition of amyloid in islet cells, leading to glucose intolerance and non-insulin-dependent diabetes mellitus, and amyloid β-protein deposition in brain cells, as associated with Alzheimer's disease. The authors conclude that there may be an overlap in the molecular defects that predispose to islet and brain amyloid, and therefore NIDDM and AD.
There is evidence of the over-expression of a protein called neural tread protein (NTP) in Alzheimer's disease neurons (see WO94/23756). This protein has been cloned (referred to as AD10-7), and expressed in cell-free culture.
The cathepsins are a family of enzymes that are usually located in lysosomes. It has been found that the inhibition of cathepsin D using an aspartyl protease inhibitor reduces the formation of β-amyloid protein and the resultant senile plaques. Thus inhibitors of cathepsin D, such as rhodanine derivatives, have been proposed as therapeutic agents for the treatment of Alzheimer's disease. See U.S. Pat. Nos. 5,716,975 and 5,523,314.
A number of companies are seeking new therapeutic agents which cross the blood-brain barrier and inhibit amyloid deposition. One such company is Athena Neurosciences, South San Francisco, who has engineered a transgenic mouse model for the disease. Athena is sorting through hundreds of molecules in a series to look for the best pharmaceutical to take into development. (Brennan.)
One drug candidate developed by Neo-Therapeutics, Irvine, Calif., is nearing clinical trials. The hypoxanthine analog (AIT-082) promotes nerve regeneration in the areas of the brain associated with memory. When the drug is administered directly to the brains of 13 month old mice, about 50% of the animals show a delay of about two months in any memory deficit and the other 50% never develop a memory deficit. This drug activates genes that express growth factor proteins known to reverse memory deficits in aged rodents when directly delivered to the brain. (Brennan.)
Another memory enhancing drug ready for clinical trials is CX516, codeveloped by Gary S. Lynch, a professor of psychobiology at the University of California, Irvine, and Gary A. Rogers, vice president of pharmaceutical discovery at Cirtex Pharmaceuticals, Irvine, Calif. CX516 is an agonist of the AMPA receptor, and promotes the uptake of Ca2+ into nerve cells when the brain levels of glutamate are low, as they are in Alzheimer's disease. This drug reversed age-associated memory impairment in rats. (Brennan.)
An over the counter agent that may lessen the symptoms or delay the progression of the disease is the nicotine patch. According to Ken Kellar, a professor of pharmacology at the Georgetown University Medical School, Washington, D.C., epidemiological data indicate that there is a lower incidence of Alzheimer's disease among people who smoke. The nicotine patch is now being tested in 12 month clinical study. (Brennan.)
Estrogen is also being evaluated as an agent that might be helpful in protecting women from Alzheimer's disease. Preliminary results indicate that women who receive estrogen replacement therapy have a lower risk of developing the disease. (Brennan.)
Another agent being evaluated is prednisone. This drug is being tested to see if it can benefit Alzheimer's patients by reducing inflammation in their brains. A further study has just been completed which examined the antioxidant effect of vitamin E and selegiline, a drug used to treat Parkinson's disease. (Brennan.)
In completely unrelated studies, it has been reported that elevated levels of insulin in the body are responsible for many cases of obesity, diabetes, heart disease, high blood pressure, and high cholesterol levels. Michael R. Eades and Mary Dan Eades, “Protein Power,” Bantam Books, New York, N.Y. (1996). Patients with any of these conditions have been successfully treated with a dietetic regimen which is designed to reduce insulin levels, primarily by strict limitation of metabolizable carbohydrate in the diet. A further strategy is to ameliorate insulin insensitivity which progresses in severity in middle age, by adding chromium to the diet. By reducing insulin insensitivity, lower levels of insulin are required by the body to clear glucose from the blood.